Hydroperoxy-desoxyhumulones

ABSTRACT

Humulones (I) are made by subjecting desoxyhumulones (II) to oxidation to form novel hydroperoxides (III) and reducing the latter. 
     The humulones are used to make known isohumulones (IV) which are bitter substances useful in the beverage industry.

FIELD OF THE INVENTION

This invention relates to the beverage field, e.g., the beer industry.

SUMMARY OF THE INVENTION

The humulones manufactured according to the present invention arecompounds of the general formula ##STR1## wherein R represents a C₁₋₆alkyl group.

According to the present invention, the compounds of formula Ihereinbefore are manufactured by oxidising a compound of the generalformula ##STR2## , wherein R has the significance given earlier,

To give a hydroperoxide of the general formula ##STR3## , wherein R hasthe significance given earlier,

And subsequently reducing a hydroperoxide of formula III to give acompound of formula I.

The compounds of formula I are intermediates for the manufacture ofknown bitter substances of the general formula ##STR4## , wherein R hasthe significance given earlier,

Into which they can be converted by isomerisation in a known manner.

The compounds of formula IV are of significance in the beverageindustry; for example, in the brewing of beer. Thus, for example, in thebrewing of beer, the humulone present in the hops (compound I with R =isobutyl) is converted into isohumulone (compound IV with R = isobutyl)during the boiling of the wort with the hops, by which means thepleasantly bitter flavour is imparted to the beer.

The process in accordance with the present invention enables thecompounds of formula I and, thus, also the compounds of formula IV, tobe manufactured in good yields, which hitherto has not been possible(Riedl, Chem. Berichte 85, 692-710, 1952).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Apart from the aforementioned isobutyl group, examples of C₁₋₆ alkylgroups are: methyl, isopropyl (compound I = cohumulone), sec-butyl(compound I = adhumulone), ethyl (compound I = posthumulone), isoamyl(compound I = prehumulone).

The hydroperoxides of formula III are novel and also form part of thepresent invention.

The oxidation of a compound of formula II to give a hydroperoxide offormula III is expediently carried out by means of elementary oxygen.

The process in accordance with the present invention (i.e. theconversion of a compound of formula II into a compound of formula I) isexpediently carried out in the presence of a base and a polar aproticsolvent, preferably at a low temperature and especially at a temperaturebelow 0° C (e.g. between 0° C and -50° C.

As bases there are preferably used very strong bases such as alkalimetal alcoholates derived from lower tertiary alkanols (e.g. potassiumt-butylate). However, alkali metal hydroxides (e.g. sodium hydroxide orpotassium hydroxide) can also be used. The base is preferably used inexcess; for example, in at least a two-fold excess.

The nature of the polar aprotic solvent is not critical and, inpractice, the choice is only limited by the fact that the solidificationpoint thereof must lie below the relatively low temperature at which theprocess is carried out. Examples of suitable polar aprotic solvents areethers (e.g. tetrahydrofuran), di(lower alkoxy)-(lower alkanes) (e.g.dimethoxyethane), amines such as di(lower alkyl)amines (e.g.dimethylamine), nitriles (e.g. acetonitrile), amides such asN,N-di(lower alkyl)amides derived from lower aliphatic carboxylic acids(e.g. N,N-dimethylformamide and N,N-dimethylacetamide) phosphoric acidderivatives (e.g. hexamethylphosphoric acid triamide) etc.

Better yields are obtained by carrying out the process in an anhydrousmedium, but the presence of a slight amount (i.e. a small percentage) ofwater does not substantially impair the yields.

For the reduction of a hydroperoxide of formula III to give a compoundof formula I there are advantageously used reducing agents which satisfythe following requirements:

1. They should not be oxidised by oxygen under the conditions employed;and

2. They should, under the conditions employed, reduce the hydroperoxideof formula III so rapidly that it does not react with a compound offormula II or I and thus lead to losses in the yields.

Especially suitable reducing agents are tri(lower alkyl)phosphites suchas, for example, triethylphosphite, trimethylphosphite ortributylphosphite.

According to a preferred embodiment of the process in accordance withthe present invention, the oxidation of a compound of formula II and thereduction of a hydroperoxide of formula III are carried out in one andthe same operation without isolation of the hydroperoxide of formulaIII; that is to say, the reducing agent is added to the mixture in totoor in part at the beginning of the process. For example, the reducingagent can be added to the mixture as the compound of formula II isconsumed and the hydroperoxide of formula III is formed therefrom. Theconsumption of the compound of formula II can be followed, for example,by chromatography (e.g. thin-layer chromatography).

According to a further preferred embodiment of the present process, analcohol (e.g. a lower alkanol) is added to the mixture. Preferredalcohols are secondary and, in particular, tertiary alcohols. Examplesare 2-propanol, 2-methyl-2-butanol and t-butanol.

The time required to complete the process can vary from several minutesto several hours (e.g. 10 hours). The course of the process can befollowed analytically (e.g. by thin-layer chromatography).

The isolation of the compounds of formula I from the mixture can becarried out according to methods known per se; for example, byextraction of the mixture diluted with a mineral acid (e.g. dilutehydrochloric acid or dilute sulphuric acid) using an organic solventsuch as an ether.

Where a compound of formula I is to be subsequently isomerised to acompound of formula IV, isolation is not necessary since the mixture canbe directly subjected to this isomerisation.

The following Examples illustrate the present invention:

EXAMPLE 1

6.64 g of desoxy-cohumulone (compound II with R = isopropyl), 5,6 g ofpotassium t-butylate, 3.65 g of triethylphosphite, 30 ml ofN,N-dimethylformamide and 20 ml of t-butanol are added under a nitrogenatmosphere to a sulphonation flask which is provided with a stirrer, gasdelivery tube and thermometer. The mixture is cooled to -30° C andoxygen is led in instead of nitrogen. After stirring for 3 hours,desoxy-cohumulone is no longer present according to thin-layerchromatographic analysis. Nitrogen is now again led in in place ofoxygen and there are carefully added to the mixture 100 ml of 2-Nhydrochloric acid. The mixture is extracted three times with 500 ml ofdiethyl ether. The combined diethyl ether extracts are washed four timeswith 250 ml of ice-water each time, dried over sodium sulphate andconcentrated under reduced pressure at 30° C. There are obtained 8.92 gof crude product which, according to chromatographic analysis, contains6.4 g of cohumulone. The by-products consist almost exclusively oftriethylphosphate which can be separated by distillation at 75° C/0.01mm Hg.

The most important data from 24 further Examples are given in thefollowing Table. Example 1 hereinbefore has been included in this Tableas No. 1. The amount of starting material of formula II is 10 mmol inall Examples with the exception of Example 1 in which the amount is 20mmol.

    __________________________________________________________________________    Examples 1-25                                                                 __________________________________________________________________________       Compd. II                                                                           Oxidising        Reducing    Temp.                                                                             Time                                                                              Crude                                                                              Compd. I                   No.                                                                              R     agent                                                                              Base Solvent                                                                              agent Alcohol                                                                             ° C                                                                        hours                                                                             product                                                                            g    Remarks               __________________________________________________________________________     1 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -30 3   8.92 6.4                                      butylate                                                                           formamide phosphite                                                                  anol                                                 2 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                                0 1.25                                                                              4.22 2.31                                     butylate                                                                           formamide                                                                            phosphite                                                                           anol                                           3 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethoxy-                                                                           Triethyl-                                                                           t-But-                                                                              -30 3   3.9  2.65                                     butylate                                                                           ethane phosphite                                                                           anol                                           4 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Tetrahydro-                                                                          Triethyl-                                                                           t-But-                                                                              -25 6.5 5.55 2.66 Acidificat-                         butylate                                                                           furan  phosphite                                                                           anol                    ion with                                                                      H.sub.2 SO.sub.4       5 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            KOH  Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -30 5   4.68 2.89                                          formamide                                                                            phosphite                                                                           anol                                           6 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Hexamethyl-                                                                          Triethyl-                                                                           t-But-                                                                              -25 2.65                                                                              4.72 2.89                                     butylate                                                                           phosphoric                                                                           phosphite                                                                           anol  -30                                                        acid tri-                                                                     amide                                                       7 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Aceto- Triethyl-                                                                           t-But-                                                                              -25 3   4.75 1.6                                      butylate                                                                           nitrile                                                                              phosphite                                                                           anol  -30                                      8 i-C.sub.3 H.sub.7                                                                   Air  K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -25 5   4.66 2.76                                     butylate                                                                           formamide                                                                            phosphite                                                                           anol  -35                                      9 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           Ethanol                                                                             -30 7   4.17 1.01                                     butylate                                                                           formamide                                                                            phosphite                                           10 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           2-Pro-                                                                              -25 6.75                                                                              4.53 2.39                                     butylate                                                                           formamide                                                                            phosphite                                                                           panol -30                                     11 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Tri-  t-But-                                                                              -28 3   3.7  2.54                                     butylate                                                                           formamide                                                                            methyl                                                                              anol                                                                    phosphite                                           12 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -50 5.5 4.24 2.19                                     butylate                                                                           amine  phosphite                                                                           anol                                          13 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           --    -30 1.5 4.39 2.17                                     butylate                                                                           formamide                                                                            phosphite                                           14 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           2-Meth-                                                                             -25 6   4.53 2.72                                     butylate                                                                           formamide                                                                            phosphite                                                                           yl-2- -30                                                                     butanol                                       15 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -15 1.25                                                                              4.77 2.6                                      butylate                                                                           formamide                                                                            phosphite                                                                           anol                                          16 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -25 2   4.59 2.7  +1 ml                               butylate                                                                           formamide                                                                            phosphite                                                                           anol  -30               H.sub.2 O             17 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -20 1   4.9  2.6                                      butylate                                                                           formamide                                                                            phosphite                                                                           anol                                          18 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                               -5 0.5 4.25 2                                        butylate                                                                           sulfoxide                                                                            phosphite                                                                           anol    0                                     19 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -40 5.5      3.27                                     butylate                                                                           formamide                                                                            phosphite                                                                           anol  -50                                     20 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            KOH  Dimethyl-                                                                            Triethyl-                                                                           --    -25 1   4.75 3.41                                          formamide                                                                            phosphite   -30                                     21 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            KOH  Dimethyl-                                                                            Triethyl-                                                                           --    -10 0.5 4.7  3.27                                          formamide                                                                            phosphite                                           22 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            KOH  Dimethyl-                                                                            Triethyl-                                                                           --     -5 0.5 4.15 2.75                                          formamide                                                                            phosphite                                           23 i-C.sub.3 H.sub.7                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -30 2.5 4.36 3.29                                     butylate                                                                           acetamide                                                                            phosphite                                                                           anol                                          24 i-C.sub.4 H.sub.9                                                                   O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -30 3   4.1  3.4                                      butylate                                                                           formamide                                                                            phosphite                                                                           anol                                          25 CH.sub.3                                                                            O.sub.2                                                                            K t- Dimethyl-                                                                            Triethyl-                                                                           t-But-                                                                              -30 3   4    2.4                                      butylate                                                                           formamide                                                                            phosphite                                                                           anol                                          __________________________________________________________________________

EXAMPLE 26

Preparation and characterisation of the hydroperoxide of formula III (R= i--C₃ H₇):

3 g of desoxy-cohumulone are dissolved in 700 ml of hexane, treated with1 g of 10% palladium on active carbon (activated by hydrogen treatment)and oxidised at -20° C for 8 hours with air-oxygen. The mixture isfiltered, the filtrate concentrated to ca 50 ml under a high vacuum(0.03 mm Hg) and at a maximum temperature of -20° C. This solution ischromatographed at -18° C on silica gel [pre-washed withmethanol/concentrated hydrochloric acid (9:1)] with pentene/ether (1:1).There is first eluted desoxy-cohumulone, then cohumulone and finally thehydroperoxide of formula III. From the thin-layer chromatogram [silicagel on glass, washed with methanol/concentrated hydrochloric acid (9:1);eluant: hexane/ether (1:1) + 1% (V/V) glacial acetic acid ], theindividual fractions produce the following results:

    ______________________________________                                                        Rf - value                                                                            FeCl.sub.3 reaction                                   ______________________________________                                        Desoxy-cohumulone 0.55      black                                             Cohumulone        0.42      blue                                              Hydroperoxide of formula III                                                                    0.24      violet                                            ______________________________________                                    

The fractions containing the hydroperoxide of formula III are combined,evaporated in vacuo at -20° C and the residue is taken up indeutero-acetone. From the NMR spectrum of this solution [60 MHz; -20° C;TMS (tetramethylsilane) as the internal standard], the following datacan be produced on the chemical shifts in comparison to cohumulone:

    __________________________________________________________________________     ##STR5##                                                                                            ##STR6##                                               A 0.95 - 1.37 ppm, m  A' 0.95 - 1.30 ppm; m                                   B 3.92 ppm, m, I = 6.5 Hz                                                                           B' 3.77 ppm, m                                          C 3.15 ppm, d, I = 7 Hz                                                                             C' 3.09 ppm, d, I = 7 Hz                                D 5.18 ppm, t, I = 7 Hz                                                                             D' 5.17 ppm, t, I = 7 Hz                                E 1.45 - 1.85 ppm, m  E' 1.45 - 1.85 ppm, m                                   F 2.52 ppm, d, I = 8 Hz                                                                             F' 2.57 ppm, d, I = 8 Hz                                G 4.87 ppm, t, I = 8 Hz                                                                             G' 5.04 ppm, t, I = 8 Hz                                Mass spectrum:                                                                Hydroperoxide III                                                             m/e: 364 (3%); 296 (49%); 253 (31%); 181 (28%); 71 (40%);                     69 (99%); 67 (18%); 59 (15%); 55 (16%); 53 (19%); 43                          (89%); 41 (100%).                                                             Cohumulone:                                                                   m/e: 348 (2%); 280 (11%); 224 (10%); 181 (9%); 69 (100%);                     53 (14%); 41 (51%).                                                           __________________________________________________________________________

EXAMPLE 27

The solution of the hydroperoxide of formula III prepared according toExample 26 is evaporated at -20° C under a high vacuum. The residue istaken up in 10 ml of benzene. 1 ml portions of this solution are shakenrespectively with the following reagents:

a. dimethylsulphide, 0.5 ml;

b. trimethylphosphite, 0.5 ml;

c. 0.2 g of sodium iodide + 0.5 ml of acetic acid + 3 ml of water.

By thin-layer chromatography of the benzene solutions, it can be shownthat in each case the hydroperoxide of formula III is reducedpractically quantitatively to cohumulone. In the case of (c), theformation of elementary iodine can also be determined.

EXAMPLE 28

The procedure described in Example 26 is repeated using desoxyhumulone(compound II with R = isobutyl) as the starting material. The resultinghydroperoxide of formula III (R = isobutyl) shows a violet FeCl₃reaction and gives the following mass spectrascopic data:

m/e: 378 (M⁺), 310, 253, 85, 69, 57.

By reduction of this hydroperoxide (R = isobutyl) with dimethylsulphidein benzene there is obtained humulone of formula I (R = isobutyl).

EXAMPLE 29

The procedure described in Example 26 is repeated usingdesoxymethyl-humulone (compound II with R = methyl). The hydroperoxideof formula III (R = methyl) is purified by preparative columnchromatography as described earlier and subjected to mass spectroscopicexamination, the following values being obtained:

m/e: 336 (M⁺), 268, 253, 69, 43.

What is claimed is:
 1. Hydroperoxides of the formula: ##STR7## wherein Rrepresents a C₁₋₆ alkyl group.
 2. A compound according to claim 1,wherein R represents the methyl group.
 3. A compound according to claim1, wherein R represents the isopropyl group.
 4. A compound according toclaim 1, wherein R represents the isobutyl group.